Adipocytokines and hepatic fibrosis

Abstract

Obesity and metabolic syndrome pose significant risk for the progression of many types of chronic illness, including liver disease. Hormones released from adipocytes, adipocytokines, associated with obesity and metabolic syndrome, have been shown to control hepatic inflammation and fibrosis. Hepatic fibrosis is the final common pathway that can result in cirrhosis, and can ultimately require liver transplantation. Initially, two key adipocytokines, leptin and adiponectin, appeared to control many fundamental aspects of the cell and molecular biology related to hepatic fibrosis and its resolution. Leptin appears to act as a profibrogenic molecule, while adiponectin has strong-antifibrotic properties. In this review, we emphasize pertinent data associated with these and other recently discovered adipocytokines that may drive or halt the fibrogenic response in the liver.

Keywords: adipocytokines; adiponectin; hepatic stellate cells; leptin; liver fibrosis.

Figure 1. Role of Leptin and adiponectin in liver fibrosis

A) Leptin acts as a profibrotic adipocytokine in liver fibrosis. The pro-fibrotic role of leptin is mediated via central effector cells of the liver, the hepatic stellate cells (HSCs). All the stages of liver fibrosis; initiation, perpetuation and resolution, are impacted by leptin. Leptin modulates initiation of liver fibrosis by priming quiescent HSCs and transforming them to activated HSCs. In the later stage known as perpetuation, leptin maintains the activated HSC phenotype and increases HSCs proliferation, impedes TRAIL-induced HSC apoptosis, and creates a molecular environment favorable for the net production of extra cellular matrix (ECM). Leptin has also been attributed to inhibit the final stage of liver fibrosis; resolution. Leptin is known to inhibit the expression of matrix metalloproteinase 1 (MMP-1) and increases the expression and activity of tissue inhibitor of metalloproteinase I (TIMP-1) —thereby inhibiting ECM degradation. Finally, leptin prohibits HSC phenotypic reversal or death. B) Adiponectin is an anti-fibrogenic adipocytokine in liver fibrosis. Adiponectin can block leptin activity by inducing suppressors of cytokine signaling 3 (SOCS3), however, adiponectin has several properties that disengage the HSC and the fibrosis process, independent of other molecules. Adiponectin can induce HSC apoptosis, and results in the loss of alpha smooth muscle (αSMA) proteins in HSCs. Still unknown is whether adiponectin pushes HSCs to partial reversion, or inactivation, or to senescence via a p53 mechanism. This mechanism has been reported to be critical to the resolution and inhibition of hepatic fibrosis from the HSC. Adiponectin also inhibits HSC proliferation and suppresses alpha collagen biosynthesis. Importantly adiponectin inhibits the transcription of tissue inhibitor of metalloproteinase I (TIMP-1); and inhibits TIMP-1 activity. Conversely adiponectin increases transcription of matrix metalloproteinase (MMP) mRNA as well as increases, in vitro, the ability of MMP-1 to degrade fibrillar collagen in matrix. Adiponectin inhibits focal adhesion kinase (FAK) activity and disrupts formation of mature focal adhesions (FA).

Figure 1. Role of Leptin and adiponectin in liver fibrosis

A) Leptin acts as a profibrotic adipocytokine in liver fibrosis. The pro-fibrotic role of leptin is mediated via central effector cells of the liver, the hepatic stellate cells (HSCs). All the stages of liver fibrosis; initiation, perpetuation and resolution, are impacted by leptin. Leptin modulates initiation of liver fibrosis by priming quiescent HSCs and transforming them to activated HSCs. In the later stage known as perpetuation, leptin maintains the activated HSC phenotype and increases HSCs proliferation, impedes TRAIL-induced HSC apoptosis, and creates a molecular environment favorable for the net production of extra cellular matrix (ECM). Leptin has also been attributed to inhibit the final stage of liver fibrosis; resolution. Leptin is known to inhibit the expression of matrix metalloproteinase 1 (MMP-1) and increases the expression and activity of tissue inhibitor of metalloproteinase I (TIMP-1) —thereby inhibiting ECM degradation. Finally, leptin prohibits HSC phenotypic reversal or death. B) Adiponectin is an anti-fibrogenic adipocytokine in liver fibrosis. Adiponectin can block leptin activity by inducing suppressors of cytokine signaling 3 (SOCS3), however, adiponectin has several properties that disengage the HSC and the fibrosis process, independent of other molecules. Adiponectin can induce HSC apoptosis, and results in the loss of alpha smooth muscle (αSMA) proteins in HSCs. Still unknown is whether adiponectin pushes HSCs to partial reversion, or inactivation, or to senescence via a p53 mechanism. This mechanism has been reported to be critical to the resolution and inhibition of hepatic fibrosis from the HSC. Adiponectin also inhibits HSC proliferation and suppresses alpha collagen biosynthesis. Importantly adiponectin inhibits the transcription of tissue inhibitor of metalloproteinase I (TIMP-1); and inhibits TIMP-1 activity. Conversely adiponectin increases transcription of matrix metalloproteinase (MMP) mRNA as well as increases, in vitro, the ability of MMP-1 to degrade fibrillar collagen in matrix. Adiponectin inhibits focal adhesion kinase (FAK) activity and disrupts formation of mature focal adhesions (FA).

Figure 2. Interplay in signal transduction between leptin and adiponectin

The profibrogenic role of leptin requires leptin-signaling via activation of the long form of leptin receptor (Ob-Rb) and the downstream Jak/Stat pathway. Conversely, adiponectin inhibits leptin signaling via activating protein tyrosine phosphate 1B (PTP1B) and suppressors of cytokine 3 (SOCS3), via the AdipoR2. Adiponectin opposes leptin signaling during the perpetuation stage of liver fibrosis by down regulating tissue inhibitor of metalloproteinase I (TIMP-1) expression and activity, along with concomitant increases in both transcriptional activation of matrix metalloproteinase 1 (MMP-1) and MMP-1 protease activity.